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Various authors have professional relationships with PEPFAR (either as employees of PEPFAR-supported US Government agencies or as grantees/contractors) as outlined in the Copyright Transfer Agreement Forms.

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It is hard to recall the world as it existed in 2003 when the President's Emergency Plan for AIDS Relief (PEPFAR) was first announced by President George W. Bush during his State of the Union address. Millions of men, women, and children around the world simply had no access to HIV care or treatment. Prevention of mother to child transmission of HIV was just an unfulfilled dream, frustrating health officials and clinicians alike. Hospital wards overflowed with the young and old lying on flimsy mattresses suffering from the many complications of HIV disease with little hope for the future. By their bedside sat family members with mournful faces, staring ahead unable to comprehend the painful reality they faced day-in and day-out. Around them health care providers hovered helplessly, unable to bring hope or solace to their patients. They were simply watching the evolution of a relentless disease while facing great fears about their own future and that of their friends and family members.

Then, seemingly overnight the world changed. In less than a decade, the skeptics have been proven wrong. No more are clinics packed with people with gaunt faces and crying babies. No more are hospital wards overwhelmed with silent children. No more are health care workers standing by in dilapidated facilities bemoaning the lack of medicines and laboratory supplies. Instead in many of the PEPFAR-focus countries, there is palpable vibrancy and unbound excitement. Millions of persons living with HIV now have access to care and treatment, millions of pregnant women can prevent transmission of HIV to their babies, millions are aware of their HIV status and have access to methods to protect themselves from acquiring or transmitting HIV. Thousands of facilities have been transformed into state-of-the-art sites where care is provided with dignity. Hundreds of thousands of health care workers have been enabled to provide high quality care, and health systems have been transformed to provide continuity care for a chronic condition like HIV. Most importantly, people living with HIV have become empowered to speak for their needs and the needs of their communities and have gained a place at the table as programs are shaped to respond to this health crisis.

Yet to date, although many reports have been written and articles published on the global HIV response, and regarding the PEPFAR response in particular, each publication has addressed only one piece of the puzzle. No cohesive cataloguing of the experience, accomplishments, and outcomes of PEPFAR since its inception has been available. As the 10-year anniversary of this initiative approaches, and the United States prepares to host the International AIDS Conference—AIDS 2012—in Washington, DC, in July, we have taken this promising and timely opportunity to critically reflect on the past nine years and explore PEPFAR's achievements and lessons learned and the challenges and opportunities ahead. To develop this Supplement, we have rapidly enlisted authors from diverse disciplines and backgrounds from around the world to present the various components of the PEPFAR response, harvest the data that are available, share insights and impressions, and offer concrete thoughts on the way forward. This effort has been complex and expansive—offering rich insights from many authors around the globe.

Topics included in this Supplement are as broad as the evolving epidemic and how it shaped the response, to specific areas of programming such as HIV testing, prevention interventions, prevention of mother to child transmission, pediatric HIV care, antiretroviral therapy and integration of HIV and tuberculosis programming. The articles in this Supplement also discuss unique features of the work including the focus on the needs of specific populations, including orphans and vulnerable children and key populations at particular risk for HIV including men who have sex with men, substance users, and sex workers. The area of health systems strengthening is also highlighted in one article as well as the critical issue of engaging communities and mobilizing civil society groups, two integral and valued aspects of the global HIV response. The Supplement is bookended by two timely articles, one providing a historic overview of PEPFAR, describing its foundation and evolution, and the other expounding on its future direction.

Multiple crosscutting themes emerge from the articles but one message resonates throughout each article. Despite the enormous challenges surrounding the HIV epidemic that existed in 2003 at the time when PEPFAR was first announced, multiple sectors of our society, both in the United States and internationally rallied in support of this global effort and successfully scaled up one of the most impressive responses to a medical and humanitarian crisis that we have witnessed in our lifetime. There is a sense of shared amazement, enthusiasm, and genuine pride at the scale of achievements on behalf of the authors, and so many others who have invested so much of themselves in these efforts.

Another theme that is palpable throughout the Supplement is the power of data and lessons learned in guiding, as time went on, informed decision making. It took several years for data to become available, and once it did, it was rapidly incorporated into program planning, implementation, and scale-up. Underscoring this theme further in the Supplement are discussions around the evolution from PEPFAR 1 to PEPFAR 2 as insights garnered from the start-up years gave way to a more streamlined and studied approach.

When the ultimate history of the HIV epidemic is written, this past decade will be recognized as a watershed time. The achievements to date by the many countries where PEPFAR works, the resources invested by PEPFAR, the Global Fund for AIDS, Tuberculosis, and Malaria, and the countries themselves, the partnerships established on the ground, the systems transformed and the infrastructures built are likely to be lauded by generations to come. Yet, the work is not done. Many more people living with HIV need to be reached, many more HIV infections must be prevented, many more partnerships need to be brokered, and many more health threats need to be tackled. The challenges ahead are enormous, particularly at a time of flat, uncertain, or declining budget levels, competing priorities and political polarization.

As governments and societies, we need to address in a measured, effective, and informed way, the highly complex and sensitive issues that have traditionally divided us: substance use, same sex partnerships, sex workers, needle exchange, family planning, reproductive health, working in an evolving political balance of power across nations although focusing on reaching those in need with great urgency. These will remain into the future critical fault lines and the core vulnerability in preserving the confidence and bipartisan support needed to sustain US leadership in the global response to HIV and other global health threats.

We cannot as a global community rest on our laurels and achievements—we must be self-critical, taking lessons learned to heart in shaping future directions while maintaining, if not accelerating, the momentum. Expansion, sustainability, and country ownership are part of the mantra of PEPFAR for the future. Only through enabling innovation, supporting flexibility, facilitating inquiry, and continued investment in the global response can we stem this epidemic and build a better future for millions around the world.